1. Respiratory Block | 1 Lecture
Globular Proteins
Respiratory Block | 1 Lecture

2. Objectives
To describe the globular proteins using common examples like hemoglobin and myoglobin.
To study the structure and functions of globular proteins like-
Hemoglobin (a major globular protein)
Myoglobin, and
g-globulins (immunoglobulins)
To know the different types of hemoglobin and difference between normal and abnormal hemoglobin
To understand the diseases associated with globular proteins

3. Globular proteins
Amino acid chains fold into shapes that resemble spheres are called globular proteins
This type of folding increases solubility of proteins in water
Polar groups on the protein’s surface
Hydrophobic groups in the interior
Fibrous proteins are mainly insoluble structural proteins

4. Globular proteins Hemoglobin: oxygen transport function
Myoglobin: oxygen storage/supply function in
heart and muscle
a1, a2, b-globulins: various functions
g-globulins (immunoglobulins): immune function
Enzymes: catalysis of biochemical reactions

5. Hemoglobin A major globular protein in humans
Composed of four polypeptide chains:
Two a and two b chains
Contains two dimers of ab subunits
Held together by non-covalent interactions
Each chain is a subunit with a heme group in the center that carries oxygen
A Hb molecule contains 4 heme groups and carries 4 molecules of O2

7. Normal: HbA (97%) HbA2 (2%) HbF (1%) HbA1c Abnormal: Carboxy Hb Met Hb
Types of Hb
Normal:
HbA (97%)
HbA2 (2%)
HbF (1%)
HbA1c
Abnormal:
Carboxy Hb
Met Hb
Sulf Hb

8. HbA structure
Oxygen binding to hemoglobin

9. Hemoglobin function Carries oxygen from the lungs to tissues
Carries carbon dioxide from tissues back to the lungs
Normal level (g/dL):
Males: 14-16
Females: 13-15

11. Types of hemoglobin Fetal hemoglobin (HbF):
Major hemoglobin found in the fetus and newborn
Tetramer with two a and two g chains
Higher affinity for O2 than HbA
Transfers O2 from maternal to fetal circulation across placenta

12. Types of hemoglobin HbA2: Appears ~12 weeks after birth
Constitutes ~2% of total Hb
Composed of two a and two d globin chains

13. Types of hemoglobin HbA1c: HbA undergoes non-enzymatic glycosylation
Glycosylation depends on plasma glucose levels
HbA1c levels are high in patients with diabetes mellitus
NH2 groups of the
N-terminal valines
of β chains

14. Abnormal Hbs Unable to transport O2 due to abnormal structure:
Carboxy-Hb: CO replaces O2 and binds 200X tighter than O2 (in smokers)
Met-Hb: Contains oxidized Fe3+ (~2%) that cannot carry O2
Sulf-HB: Forms due to high sulfur levels in blood (irreversible reaction)

15. Hemoglobinopathies Synthesis of structurally abnormal Hb
Disorders of hemoglobin caused by:
Synthesis of structurally abnormal Hb
Synthesis of insufficient quantities of normal Hb
Combination of both

16. Hemoglobinopathies Sickle cell (HbS) disease
Caused by a single mutation in b-globin gene
Glutamic acid at position 6 in HbA is replaced by valine
The mutant HbS contains bs chain
The shape of RBCs become sickled
Causes sickle cell anemia

17. Hemoglobinopathies Hemoglobin C disease:
Caused by a single mutation in b-globin gene
Glutamic acid at position 6 in HbA is replaced by lysine
Causes a mild form of hemolytic anemia

18. Hemoglobinopathies Methemoglobinemia:
Caused by oxidation of Hb to ferric (Fe3+) state
Methemoglobin cannot bind oxygen
Caused by certain drugs, reactive oxygen species and NADH-cytochrome b5 reductase deficiency
Chocolate cyanosis: brownish-blue color of the skin and blood

19. Hemoglobinopathies Thalassemia:
Defective synthesis of either a or b-globin chain due to gene mutation
a-thalassemia:
Synthesis of a-globin chain is decreased or absent
Causes mild to moderate hemolytic anemia
b-thalassemia:
Synthesis of b-globin chain is decreased or absent
Causes severe anemia
Patients need regular blood transfusions

20. Myoglobin A globular hemeprotein in heart and muscle
Stores and supplies oxygen to the heart and muscle only
Contains a single polypeptide chain forming a single subunit with eight a-helix structures
The interior of the subunit is composed of nonpolar amino acids

21. Myoglobin The charged amino acids are located on the surface
The heme group is present at the center of the molecule
Myoglobin gives red color to skeletal muscles
Supplies oxygen during aerobic exercise

22. Structure of myoglobin

23. Myoglobin in disease
Myoglobinuria: Myoglobin is excreted in urine due to muscle damage (rhabdomyolysis)
May cause acute renal failure
Specific marker for muscle injury
Less specific marker for heart attack

24. Immunoglobulins
Defensive proteins produced by the B-cells of the immune system
Y-shaped structure with 2 heavy and 2 light polypeptide chains
Neutralize bacteria and viruses
Types: IgA, IgD, IgE, IgG, IgM

25. Take Home Messages
Amino acid chains fold into shapes that resemble spheres are called globular proteins.
Fibrous proteins are mainly insoluble, while globular proteins are soluble structural proteins.
Hb, Myoglobin, globulines and enzymes are examples of globular proteins.
Functionally, Hb is for O2 and CO2 transport.
HbA, HbA2 and HbF are examples of normal Hb, in which the tetrameric structure is composed of 2α constant subunits with 2 changeable β subunits according to Hb type.

26. Take Home Messages
HbA1C is a HbA which undergoes non-enzymatic glycosylation, depending on plasma glucose levels.
Carboxy-Hb, Met-Hb and Sulf-Hb are examples of abnormal Hb, in which O2 molecules are not transported due to abnormal Hb structure.
Disorders of Hb caused by synthesis of structurally abnormal Hb and/or insufficient quantities of normal Hb.
Sickle cell (HbS) and HbC diseases are caused by a single mutation in β-globin gene.

27. Take Home Messages
Glu6 in HbS is replaced by Val, while it is replaced by Lys in HbC.
Methemoglobinemia is caused by oxidation of Hb, inhibiting O2 binding leading to chocolate cyanosis.
Thalassemia is caused by a defect in synthesis of either α- or β-globulin chain, as a result of gene mutation.
α-Thalassemia causes less sever anemia than β-Thalassemia.
Myoglobin is a globular hemeprotein, which stores and supplies O2 to the heart and muscle only.

28. Take Home Messages
Hb is composed of 4 chains (subunits), while Myoglobin is composed of a single chain.
Myoglobinuria is a specific marker for muscle injury and may cause acute renal failure.
Immunoglobulins are defensive proteins produced by the B-cells.
Immunoglobulins consist of 5 types: IgA, IgD, IgE, IgG and IgM.

29. References
Illustrations in Biochemistry by Lippincott 6th edition.